This invention relates to an improved process for the preparation of xylazine. More particularly, the invention is directed to an improvement in the production of an isothiocyanate intermediate (2,6-dimethlyphenylisothiocyanate) used in the preparation of xylazine.
Xylazine is a well known sedative, analgesic, and muscle relaxant, and has been produced by various alternatives synthesis. One of the most common synthesis sequences is listed below: ##STR1##
The reaction sequence shown involves the reagent thiophosgene which gives high yields of the intermediate 2,6-dimethylphenylisothiocyanate directly from 2,6-dimethylaniline. However, this synthesis is undesirable because of the toxicity of thiophosgene, and because thiophosgene has now become prohibitively expensive and nearly unavailable in bulk quantities.
A second reaction sequence is provided in the U.S. Pat. No. 4,614,798 to Elliott, et al., and is as follows: ##STR2##
However, the reaction sequence shown is not desirable because of dangers associated with both handling large amounts of sodium hydride and the evolution of large volumes of hydrogen gas during the addition of the hydride to the solution containing 2,6-dimethylacetanilide. Another disadvantage arises because at the evolution of heat and vigorous foaming during the addition of sodium hydride, with the potential of a runaway reaction. Yet another disadvantage arises because the potential for an explosion exists during the quenching of the reaction mixture with water after the addition of carbon disulfide if residual sodium hydride is present.
A final disadvantage arises in the distillation of the isothiocyanate from this reaction sequence. Difficulty is often encountered during the distillation due to the presence of unconverted 2,6-dimethylacetanilide. The latter compound distills at a temperature similar to that temperature at which the isothiocyanate distills, and complicates the distillation due to solidification of 2,6-dimethylacetanilide in the distillation head.
Thus, because the synthesis of xylazine according to the present invention does not involve the addition of a moisture sensitive and potentially pyrophoric reagent such as sodium hydride to the reaction mixture with the dangers associated with the evolution of hydrogen and foaming, it is well suited for large scale production of xylazine. Furthermore, because of the nature of the isothiocyanate intermediate formed with the method of the present invention, the ease of purification of the associated intermediate by vacuum distillation is improved.